Project 3: Mouse Models of Smoking-related Diseases: What is the Best

项目 3：吸烟相关疾病的小鼠模型：什么是最好的

• 批准号: 8904705
• 负责人: Claire M Doerschuk
• 金额: $ 80.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904705
• 关键词: Address; Animal Model; Biological Assay; Cells; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigar; Cigarette; Code; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Dehydration; Disease; Drug Metabolic Detoxication; Employee Strikes; Epithelial; Epithelial Cells; Foamy Macrophage; Gene Expression Profiling; Genes; Goals; Haemophilus influenzae; Health; Human; Immune; Immunophenotyping; Inflammation; Injury; Interstitial Lung Diseases; Liquid substance; Literature; Lung; Lung diseases; Lymphocyte Count; Malignant neoplasm of lung; Marketing; Matrix Metalloproteinases; Mediastinal lymph node group; Messenger RNA; Metaplasia; MicroRNAs; Modeling; Mouse Strains; Mucins; Mucociliary Clearance; Mucous body substance; Mus; Natural Immunity; Obstruction; Outcome; Pathology; Pathway interactions; Patients; Pneumonia; Population; Production; Proteins; Pulmonary Emphysema; Regulatory Pathway; Reporter; Research; Signal Pathway; Smoke; Smoking; System; Testing; Tobacco; Tobacco smoke; Toxic effect; Transgenic Mice; Water; Wild Type Mouse; Work; absorption; base; cell type; cigarette smoking; cytokine; human disease; in vivo; interest; lung injury; macrophage; mouse model; mucus hypersecretion; neutrophil; overexpression; tobacco exposure

Tobacco smoke has a devastating impact on health, particularly on lung health. It is the most common cause of chronic obstructive lung disease (COPD) and lung cancer. It also has synergistic effects on numerous other lung diseases, including interstitial lung disease and pneumonia. Most mouse models oftobacco smokerelated lung disease expose mouse strains to tobacco smoke. This model usually results in mild-to-moderate emphysema, but little or no evidence ofthe chronic bronchitis, which is a large component of COPD in humans. Our aim is to establish a model oftobacco smoke-induced lung injury that mimics that found in humans. This work will address the FDA CPT research interest, "Adverse Health Consequences". The goal ofthis project is to determine what animal models can be validated to establish standard toxicity changes and what magnitude observed within in vivo assays correlates with change in human health outcome (point 31). As described in Project 1, smoke exposure leads to decreased activity of CFTR, resulting in absorption of water from airway liquid, dehydration of mucus, and poor mucociliary clearance. Transgenic mice overexpressing Scnnib, the gene which codes forthe epithelial Na* chanriel subunit (pENaC), in the epithelial cells ofthe airways mimic this aspect oftobacco smoke, showing mucus cell metaplasia, mucus hypersecretion and obstruction, neutrophilic inflammation, large foamy macrophages, and increased numbers of lymphocytes in both the lumen and the walls ofthe ainways. These mice also show evidence of an MMP-12-dependent emphysematous component to the injury. Thus, the lungs of these mice develop pathology that mimics changes found in COPD patients, highlighting the striking effects of airway dehydration. However, these mice are missing all other effects oftobacco smoke, which are likely to be many due to numerous components of tobacco smoke. We are modeling tobacco smoke exposure in humans by exposing Scnn1b-tg mice to prolonged (6 month) tobacco smoke exposure. Our studies to date suggest that this model mimics the human injury more closely than mouse models to date. In particular, gene expression analysis suggests that smoke exposure in Scnnlb-ig mice results in more similarities to human disease in both detoxification pathways and in immune regulatory pathways. Other similarities to date include changes in mucins within the airways and the presence of large numbers of vesicular exosomes. Thus, we propose to test the hypothesis that smoke exposure in Scnn1b-tg mice is an excellent model of human disease and can be used more effectively than either wild type (WT) mice or other mouse models of COPD to study particular components of smoke or to compare tobacco products or substitutes.

烟草烟雾对健康，特别是对肺部健康具有破坏性影响。这是最常见的原因 慢性阻塞性肺疾病（COPD）和肺癌。它还对许多其他方面产生协同效应， 肺部疾病，包括间质性肺病和肺炎。大多数与烟草烟雾有关的小鼠模型 肺部疾病使小鼠品系暴露于烟草烟雾。这种模式通常会导致轻度至中度 肺气肿，但很少或没有证据表明慢性支气管炎，这是一个很大的组成部分，慢性阻塞性肺疾病在人类。 我们的目的是建立一个烟草烟雾诱导的肺损伤模型，模拟人类的肺损伤。这 工作将解决FDA CPT研究兴趣“不良健康后果”。这个项目的目标是 以确定哪些动物模型可以验证，以建立标准的毒性变化， 在体内试验中观察到的幅度与人类健康结果的变化相关（第31点）。 如项目1中所述，烟雾暴露导致CFTR活性降低，导致吸收 来自气道液体的水、粘液脱水和粘膜纤毛清除不良。转基因小鼠 过度表达Scnnib，编码上皮Na* chanriel亚单位（pENaC）的基因， 气道上皮细胞模仿烟草烟雾的这一特征，表现为粘液细胞化生， 分泌过多和阻塞，嗜酸性炎症，大泡沫状巨噬细胞， 淋巴细胞数量在腔和壁的动脉。这些老鼠也显示出 损伤的一种MMP-12依赖性肺气肿成分。因此，这些小鼠的肺发育 模拟COPD患者中发现的变化的病理学，突出了气道 脱水然而，这些小鼠没有受到烟草烟雾的其他影响， 许多是由于烟草烟雾的多种成分。我们正在模拟烟草烟雾暴露， 通过将Scnn 1b-tg小鼠暴露于长期（6个月）烟草烟雾暴露，我们迄今为止的研究 表明该模型比迄今为止的小鼠模型更接近于模拟人类损伤。特别是基因 表达分析表明，烟雾暴露在Scnnlb-ig小鼠中导致与人类更多的相似性， 疾病的解毒途径和免疫调节途径。迄今为止的其他相似之处包括 气道内粘蛋白的变化和大量囊泡外泌体的存在。因此我们 我建议检验这一假设，即在Scnn 1b-tg小鼠中暴露于烟雾是一个很好的人类模型。 并且可以比野生型（WT）小鼠或其他COPD小鼠模型更有效地用于 研究烟雾的特定成分或比较烟草产品或替代品。